Selective omission of sentinel lymph node biopsy in mastectomy for ductal carcinoma in situ: identifying eligible candidates

Background Sentinel lymph node biopsy (SLNB) is recommended for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy, given the concerns regarding upstaging and technical difficulties of post-mastectomy SLNB. However, this may lead to potential overtreatment, considering favorable prognosis and de-escalation trends in DCIS. Data regarding upstaging and axillary lymph node metastasis among these patients remain limited. Methods We retrospectively reviewed patients with DCIS who underwent mastectomy with SLNB or axillary lymph node dissection at Gangnam Severance Hospital between January 2010 and December 2021. To explore the feasibility of omitting SLNB, we assessed the rates of DCIS upgraded to invasive carcinoma and axillary lymph node metastasis. Binary Cox regression analysis was performed to identify clinicopathologic factors associated with upstaging and axillary lymph node metastasis. Results Among 385 patients, 164 (42.6%) experienced an invasive carcinoma upgrade: microinvasion, pT1, and pT2 were confirmed in 53 (13.8%), 97 (25.2%), and 14 (3.6%) patients, respectively. Seventeen (4.4%) patients had axillary lymph node metastasis. Multivariable analysis identified age ≤ 50 years (adjusted odds ratio [OR], 12.73; 95% confidence interval [CI], 1.18–137.51; p = 0.036) and suspicious axillary lymph nodes on radiologic evaluation (adjusted OR, 9.31; 95% CI, 2.06–41.99; p = 0.004) as independent factors associated with axillary lymph node metastasis. Among patients aged > 50 years and/or no suspicious axillary lymph nodes, only 1.7–2.3%) experienced axillary lymph node metastasis. Conclusions Although underestimation of the invasive component was relatively high among patients with DCIS undergoing mastectomy, axillary lymph node metastasis was rare. Our findings suggest that omitting SLNB may be feasible for patients over 50 and/or without suspicious axillary lymph nodes on radiologic evaluation. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-024-01816-7.


Introduction
Ductal carcinoma in situ (DCIS) is a noninvasive neoplastic lesion of the breast, comprising approximately 25% of all newly diagnosed breast cancers [1][2][3].As DCIS is characterized by the proliferation of malignant epithelial cells confined within the basement membrane [3], patients with DCIS who receive appropriate treatment have an excellent prognosis.According to a previous study assessing over 100,000 patients with DCIS from the Surveillance, Epidemiology, and End Results database, the 20-year breast cancer mortality was only 3.3% [4].Furthermore, the risk of ipsilateral invasive recurrence at 20 years was 5.9%, and that of contralateral invasive recurrence at 20 years was 6.2%.Despite these characteristics, mastectomy has been performed in at least 20% of patients with DCIS, especially those with extensive or multifocal/multicentric lesions [4].
Axillary lymph node metastasis has long been considered a critical prognostic factor to guide systemic therapy or radiotherapy in patients with invasive breast cancer [5].Sentinel lymph node biopsy (SLNB) is currently the standard surgical procedure to determine axillary staging [6,7].To ameliorate surgical complications and improve the patient's quality of life by reducing axillary intervention, several ongoing prospective randomized trials are exploring the possibility of omitting SLNB in early breast cancer [8,9].
Regarding axillary surgery in DCIS, SLNB is unessential in most patients with pure DCIS undergoing breast-conserving surgery.Conversely, SLNB is strongly recommended for patients diagnosed with DCIS requiring mastectomy owing to the following concerns [3]: (i) patients with DCIS who undergo a mastectomy have a high probability of upgrading to invasive breast cancer, and (ii) mastectomy can permanently alter the lymphatic drainage pattern, hampering the performance of additional SLNB if invasive breast cancer is confirmed unexpectedly in patients who had undergone mastectomy alone.We hypothesized that a substantial portion of patients diagnosed with DCIS and requiring mastectomy could potentially omit SLNB.However, limited data exists regarding the incidence of upgrade to invasive breast cancer and axillary lymph node metastasis in patients diagnosed with DCIS who underwent mastectomy.
This study aimed to assess the prevalence of upgrade to invasive breast cancer and axillary lymph node metastasis in patients who were diagnosed with DCIS on biopsy and subsequently underwent mastectomy with axillary surgery to establish the need for SLNB.Furthermore, we explored the clinicopathologic features related to the upgrade to invasive breast cancer and axillary lymph node metastasis.

Study population
The study protocol was reviewed and approved by the Institutional Review Board of the Gangnam Severance Hospital, Yonsei University, Seoul, Korea (IRB no.3-2023-0026), and adhered to the tenets of the Declaration of Helsinki.The requirement for written informed consent was waived owing to the retrospective study design.The study was registered as a retrospective study on ClinicalTrials.gov,trial number NCT05961280.

Clinicopathologic features
We reviewed the electronic medical records to collect pre-and postoperative patient characteristics.Preoperative characteristics included age at diagnosis, presenting clinical symptoms (palpable mass or bloody nipple discharge), radiologic findings (clinical tumor size and the presence of suspicious axillary lymph node and microcalcification), and the pathologic findings from the biopsy samples (nuclear grade and comedo necrosis).Postoperative characteristics included pathologic findings from surgical specimens, such as pathologic DCIS size; nuclear grade (NG); comedo necrosis; status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67; and axillary lymph node metastasis.According to ER, PR, and HER2 results, we classified the patients into hormone receptor (HR) positive or negative and HER2 positive or negative.Additionally for descriptive purposes, three DCIS subtypes were divided in supplementary analyses: hormone receptor (HR)-positive/HER2-negative (HR + HER2-), HER2-positive (HER2+), and HR-negative/Her2-negative (HR-HER2-) DCIS.All patients underwent mammography, ultrasound, and breast magnetic resonance imaging (MRI) before the curative surgery.Based on the imaging reports, clinical tumor size was defined as the largest tumor size among the mammography, ultrasound, and breast MRI assessments.Additionally, a suspicious axillary lymph node on radiologic evaluation was defined as the presence of an axillary lymph node with suspicious features in any one of the assessments (i.e., mammography, ultrasound, and breast MRI).We defined the following criteria as indicative of suspicious axillary lymph nodes: (i) cases where an axillary lymph node showed dense obliterated hila and cortical thickness visible on mammography, and (ii) cases where an axillary lymph node exhibited loss of the fatty hilum, a round shape, or eccentric cortical thickening on ultrasound or breast MRI.Among the patients with radiologically suspicious axillary lymph node, few patients (14 of 89 [15.7%]) underwent fine needle aspiration biopsy (FNAB) and all were confirmed negative.

Statistical analyses
Our primary objective was to identify the axillary lymph node metastasis rate in patients with DCIS at diagnosis who underwent mastectomy with axillary surgery.We also assessed the upgrade rate of DCIS to invasive breast cancer.Axillary lymph node metastasis was defined as macrometastasis (size of most extensive metastatic lesion > 2 mm) and micrometastasis (size of most extensive metastatic lesion 0.2-2 mm) according to the American Joint Committee on Cancer guidelines (eighth edition).DCIS upgraded to invasive disease was defined as the diagnosis of invasive breast carcinoma in mastectomy specimens, including microinvasion.
Discrete variables according to axillary lymph node metastases and DCIS upgraded to invasive disease were compared using the chi-square or Fisher exact test.Univariable and multivariable analyses were performed using a binary logistic regression model to identify the predictive clinicopathologic features for axillary lymph node metastasis and DCIS upgrade to invasive disease.Odds ratio (OR) and 95% confidence interval (CI) with twosided p-values were determined.Factors considered in the multivariable analysis included age (≤ 50 vs.> 50), Symptoms with a palpable mass or bloody nipple discharge (no vs. yes), clinical tumor size (as a continuous variable), radiologically suspicious axillary lymph node (no vs. yes), radiologically suspicious microcalcification (no vs. yes), nuclear grade (low vs. intermediate vs. high), HR status (negative vs. positive), HER2 status (negative vs. positive), and Ki-67 (< 14% vs. ≥ 14%).Data analyses were performed using SPSS version 25 (IBM Corp., Armonk, NY, USA), and a p-value of < 0.05 defined statistical significance.

Discussion
Surgical de-escalation is an important topic that is actively being discussed in the field of breast cancer.
Although SLNB is a minimally invasive procedure, it is frequently associated with considerable short-term treatment-related upper limb morbidity, including lymphedema, pain, reduced range of motion, and muscle weakness [10,11].A growing body of literature indicates that SLNB can be omitted in patients initially diagnosed with DCIS [12][13][14][15][16][17][18].Accordingly, the current guidelines suggest that axillary staging can be omitted in patients with DCIS undergoing breast-conserving surgery.Furthermore, several ongoing clinical trials are attempting to compare active surveillance to standard therapy in low-risk DCIS [19,20].Although DCIS has a less aggressive phenotype, most patients with DCIS who need mastectomy undergo SLNB owing to concerns regarding upgrade to invasive breast cancer and technical difficulty in performing SLNB after the removal of breast tissues.
Thus, there is still an unmet need for axillary surgery omission in this subpopulation.
In this study, we investigated the incidence of upgraded pathologic stage from DCIS to invasive breast cancer and axillary lymph node metastasis in patients with DCIS who underwent mastectomy.Patients with DCIS upgrade to invasive cancer comprised approximately 42% of our study cohort, which was relatively higher than that in previous studies (21.8-37.1%)[15,21,22].This discrepancy could be attributed to the inclusion of patients who underwent excision or breast-conserving surgery in previous studies, whereas ours predominantly focused on the patient population who underwent mastectomy.Consistent with the finding of a previous study [18], large tumor size and a palpable mass or bloody nipple discharge were risk factors for upgrade to invasive breast cancer.
Although the upgrade to invasive breast cancer occurred in a substantial number of patients, the actual axillary lymph node metastasis rate was only 4.4%.Consistently, a Danish group has speculated that the overall metastatic lymph node rate was < 9% in a nationwide study [17].Another study revealed that 2.7% of patients who undergo mastectomy for DCIS had axillary lymph node metastasis on final pathology [16].Moreover, similar to previous literature [18], we found that a younger age (≤ 50 years) and suspicious axillary lymph nodes on preoperative radiologic evaluation were independent predictors for axillary lymph node metastasis.The axillary lymph node metastasis rate was further reduced to 1.7-2.3%among females aged > 50 years and/or those lacking any suspicious axillary lymph nodes on radiologic evaluation.The recently published SOUND trial [23], although consisting of a different cohort of patients who underwent breast-conserving surgery for invasive breast cancer, showed that omitting SLNB in patients with early breast cancer did not result in inferior survival compared to the SLNB arm, with a primary 5-year distant disease-free survival rate of 98% vs. 97.7%(non-inferiority p = 0.02).In addition, the node-positive rate was relatively low (13.7%) in the SLNB arm.Nearly 95% of patients in the SOUND trial were classified as pT1.Similarly, 91% of patients who experienced an upgrade from DCIS to invasive breast cancer were also categorized as pT1 in our study.Considering the clinical implications of these findings, it may be safe to omit SLNB in patients with DCIS undergoing mastectomy if the aforementioned criteria are met.Ongoing studies on de-escalation of axillary surgery will provide further insights [24].A novel surgical strategy may be an alternative approach in patients diagnosed with DCIS presenting the risk factors for axillary lymph node metastasis.Superparamagnetic iron oxide (SPIO) nanoparticles, an SLN tracer, showed comparable performance to the conventional radioisotope (Technetium 99m [Tc 99 ]) and blue The p-value was determined using Fisher's exact test § Values assessed in surgical specimens dye [25,26].The half-life of Tc 99 is short (approximately 6 h), whereas SPIO nanoparticles can reside within the sentinel lymph nodes for a prolonged duration.This unique characteristic of SPIO nanoparticles could facilitate delayed SLNB as a secondary operation after primary breast surgery [27].In the SentiNot trial, applying SPIO nanoparticles reduced unnecessary upfront SLNB by 78.3% in patients with a preoperative diagnosis of DCIS [28].Among patients who underwent delayed SLNB, the SPIO nanoparticle group had higher sentinel lymph node detection rates than the Tc 99 group.Considering only those patients who underwent mastectomy, the detection rates were 83.3 and 22.0% for the SPIO and Tc 99 groups, respectively.Despite the requirement for a secondary surgical procedure and the limited adoption of SPIO, the option of a delayed SLNB with SPIO nanoparticle injection can be contemplated for patients with DCIS undergoing mastectomy, specifically those with age under 50 years and radiologically suspicious axillary lymph node.
Our study had several limitations.First, our study exclusively included patients who underwent mastectomy for DCIS in this study, potentially introducing selection bias.Moreover, due to the retrospective nature of the study, we could not identify cases where mastectomy was performed at the patient's request.However, it's worth noting that only about 15% of the patients (60 out of 385) were eligible for partial mastectomy for a tumor size smaller than 2 cm.Moreover, considering the median clinical tumor size was 4.5 cm, it is reasonable to assume that most patients likely underwent mastectomy due to factors such as large tumor size, multiple or widespread microcalcifications, or clinical nipple involvement.Consequently, clinical symptoms like palpable mass and bloody nipple discharge seemed to occur relatively frequently.Second, it is necessary to evaluate the usefulness of FNAB in predicting axillary lymph node metastasis.Given that FNAB-positive patients were classified as having invasive breast cancer, these cases were Of the 14 patients who underwent FNAB, one (7.1%)had axillary lymph node metastasis.Lastly, we cannot evaluate the oncologic safety of SLNB omission in these patients, as all patients received SLNB or SLNB followed by ALND in the current study.Hence, further prospective clinical trials are warranted to confirm the safety of omitting SLNB in the examined patient population.
In conclusion, although the axillary lymph node metastasis rate was low (4.4%), approximately 40% of patients with a preoperative diagnosis of DCIS who underwent mastectomy experienced upgrade to invasive breast cancer.Notably, axillary lymph node metastasis was rarely observed in patients aged > 50 years and/or in those without any suspicious lymph nodes on preoperative radiologic evaluation.Our real-world data suggest that the omission of SLNB may be feasible in these specific subpopulations.Further investigations with a prospective design and a more substantial sample size should be considered to comprehensively validate these findings.

Fig. 1
Fig. 1 Flow diagram of the study population

Fig. 3
Fig. 3 The rate of axillary lymph node (ALN) metastasis in (A) patients aged ≤ 50 (B) patients aged > 50, (C) patients without suspicious ALN on radiologic evaluation and (D) patients with suspicious ALN on radiologic evaluation.ALN, axillary lymph node

Table 1
Baseline characteristics * Missing values † Values assessed in biopsy specimens ‡ Values assessed in surgical specimens DCIS = ductal carcinoma in situ, HR = hormone receptor, HER2 = human epidermal growth factor receptor 2Fig. 2 Pathologic results regarding the upgrade to invasive breast cancer.DCIS, ductal carcinoma in situ Axillary

Table 2
Baseline characteristics according to DCIS upgraded to invasive disease * Missing values † Values assessed in biopsy specimens § Values assessed in surgical specimens

Table 3
Odds ratio (OR) and 95% confidence interval (CI) for DCIS upgraded to invasive disease * Missing values † Values assessed in biopsy specimens § Values assessed in surgical specimens

Table 4
Baseline characteristics according to axillary lymph node metastasis * Missing values † Values assessed in biopsy specimens ‡

Table 5
Odds ratio (OR) and 95% confidence interval (CI) for axillary lymph node metastasis Missing values † Values assessed in biopsy specimens § Values assessed in surgical specimens excluded.Moreover, the implementation rate of FNAB was low: patients without suspicious axillary lymph nodes on radiologic evaluation did not undergo FNAB, and only 14 of 89 (15.7%) patients with suspicious axillary lymph nodes on radiologic evaluation underwent FNAB. *

Table 6
Pathologic axillary lymph node metastasis by age and the presence of radiologically suspicious axillary lymph node